Novel allyl carbamates



United States Patent 3,531,511 NOVEL ALLYL CARBAMATES Donald R. Cassady,Robert D. Dillard, and Nelson R. Easton, Indianapolis, Ind., assignorsto Eli Lilly and Company, Indianapolis, Ind., a corporation of IndianaNo Drawing. Continuation-impart of application Ser. No. 533,405, Mar.11, 1966. This application Oct. 13, 1967, Ser. No. 675,058

Int. Cl. C07c 25/06; C07d 27/02, 29/24 U.S. Cl. 260-468 6 ClaimsABSTRACT OF THE DISCLOSURE Novel allyl carbamates, useful for theirantibacterial and antiviral properties.

BACKGROUND OF THE SPECIFICATION This is a continuation-in-part ofapplication Ser. No. 533,405, filed Mar. 11, 1966 now Pat. No.3,436,402, which application is a continuation-in-part of applicatitonSer. No. 421,677, filed Dec. 28, 1964, now abancloned.

SUMMARY This invention relates to certain novel carbamates. Thecompounds provided by this invention can be represented by the followingformula:

wherein R and R when taken separately, are phenyl, tolyl,monohalophenyl, naphthyl, xenyl, trifluoromethylphenyl, or pyridyl, andwhen taken together with the carbon atom to which they are attached,fluorenyl, wherein the ethylenic function is attached directly to the 9-position of the fiuorenyl radical; Am is -NR R wherein R R and R arehydrogen, C -C alkyl, C -C hydroxyalkyl, di-lower-alkylamino-1oweralkyl, C C alkenyl, C -C alkynyl, C 0 cycloalkyl, or C -C bicycloalkyl,

Lower alkyl, as used herein, is to be understood to mean C -C alkyl viz,methyl, ethyl, n-propyl, and isopropyl.

C -C alkyl includes methyl, ethyl, n-propyl, isopropyl, n-butyl,sec.-butyl, tert.-butyl, isobutyl, n-amyl, isoamyl, neopentyl, n-hexyl,isohexyl, and the like.

C -C alkynyl refers to the C C alkyl groups, as defined, from which twohydrogen atoms have been removed from each of two adjacent carbon atomsto produce acetylenic unsaturation, e.g., propargyl, 2-butynyl,l-pentynyl, 3-hexynyl, and the like.

C -C alkenyl refers to the C -C alkyl groups, as defined, from which ahydrogen atom has been removed from each of two adjacent carbon atoms toproduce ethylenic unsaturation, e.g., allyl, methallyl, l-pentenyl, 2-hexenyl, and the like.

C -C cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, and cyclooctyl.

Patented Sept. 29, 1970 C -C bicycloalkyl refers tobicyclo[2.l.0]pentyl, bicyclo[2.2.0]hexyl, bicyclo[1.2.1]hexyl,norbornyl, bicyclo[2.2.2]octyl, and the like.

Halo refers to fluoro, ehloro, bromo, and iodo.

Lower-alkoxy refers to C -C alkoxy, and includes methoxy, ethoxy,n-propoxy, and isopropoXy.

Lower-alkylamino refers to C -C alkylamino, and includes methylamino,ethylamino, n-propylamino, and isopropylamino.

Di-lower-alkylarnino refers to di(C -C alkyl) amino, and includesdimethylamino, diethylamino, di-npropylamino, and diisopropylamino, aswell as the mixedalkyl dialkylamines, e.g., methylethylamine,methylisopropylamine, ethyl-n-propylamine, and the like.

Representative compounds provided by this invention include thefollowing:

1,1-diphenylallyl N-ethylcarbamate 1,1-diphenylallylN,N-dimethylcarbamate l-phenyl-l-(p-tolyl)a1lyl carbamate1-phenyl-1-(4-bromophenyl)allyl carbamate 1,1-diphenylallyl carbamate 1-(4-bron10phenyl l-phenylallyl N-methylcarbamatel-(3-chlorophenyl)-l-phenylallyl carbamate 1-( 3-chl0rophenyl)-1-pheny1allyl N,N-dimethyl-carbamate 1-(3-chlorophenyl)-l-phenylallylN-methylcarbamate 1,1-diphenylallyl N- 2propynyl) carbamate1,1-diphenylallyl N-cyclopropylcarbamate1-(2-chlorophenyl)-l-phenylallyl carbamate l-phenyl- 1- Z-pyridyl allylN-methylcarb amate 1- 4-fiuorophenyl l -phenylallyl N,N-dimethy1-carbamate 1(4-fluorophenyl)-1-phenylallyl carbamatel(2-naphthyl)-1-phenylallyl 1-pyrrolidinecarboxylate l-phenyl- 1(p-ehlorophenyl allyl carbamate 1,1-diphenyla1lyl N-3-dimethylaminopropyl carb amate l-phenyl-l-(4-biphenylyl)allylcarbamate l-(3-bromophenyl)-l-phenylallyl carbamate1-(3-bromophenyl)-1-phenylallyl N,N-dirnethylcarbamate 1,1-diphenylallylN-methylcarbamate 9-vinyl-9-fiuorenyl N-methylcarbamate1-(3-chlorophenyl)-1-phenylallyl carbamate l-(4-bromophenyl-1-phenylallyl 1'-pyrrolidinecarboxylate 1,1-diphenylallyl4'-(Z-hydroxyethyl)-1-piperazinecarboxylate 1, l-diphenylallyl-4-methyll'-piperazinecarboxylate l-phenyl-l-(Z-naphthyl)allylN,N-dimethylcarbamate l-(4-chlorophenyl)-l-phenylallyl1'-pyrrolidinecarboxylate 1,1-diphenylallyl 1'-piperidinecarb0xylate9-vinyl-9-fluoroenyl N,N-dimethylcarbamate 1 -phenyl-1- (2-pyridyl)allyl N,N-dimethylcarb amate 1-(4-chl0rophenyl)-1-phenylallylN-methylcarbamate 1,1-diphenylallyl 4'-rnorpholinecarboxylate1,1-diphenylallyl N-cyclohexylcarbamate1-(4-fluorophenyl)-1-phenyl-5-diethylarnino Z-pentenyl-N-cyclopropylcarbarnate 1, l-bis (4-fiuorophenyl allylN-norbornylcarbamate 1,1-diphenylallyl N-bicyclo[2.2.2]octyl carbamateCompounds represented by the above formula can be prepared from theacetylenic derivatives thereof, which compounds are prepared by methodswell-known to those skilled in the art, such as the methods of Ensslinand Meier, US. Pat. No. 2,798,885; Marshall et al., US Pat. No.2,814,637; and Mehla and Catlin, U.S. Pat. No. 3,062,870; and by ourcopending application, Ser. No. 533,405, filed March 1966. Thesemi-reduced ethylenic derivatives are then prepared by catalytichydrogenation in the presence of a heavy metal as for example 5%palladium on barium sulfate or 5% palladium on calcium carbonate in thepresence of a solid base such as powdered potassium hydroxide, and asdescribed in this specification. A general procedure which can be usedfor the preparation of the acetylenic carbamates used in the examplesbelow is herein illustrated:

1-(4-bromopheny1-1-phenyl-2-propynyl carbamate A mixture of 57.4 g. of1-(4-bromophenyl)-1-phenyl- 2-propyn-1-ol, 80 ml. of pyridine, and 200ml. of dichloromethane was cooled to C. and treated with 31.3 g. ofphenyl chloroformate dropwise with stirring over a onehour period. Thereaction mixture was stirred 4 additional hours and 200 ml. of waterwere added cautiously. Extraction of the crude product with 500 ml. ofdiethyl ether, separation of the ether layer, and washing the etherlayer with 100 ml. of 5 N HCl followed by 100 ml. saturated sodiumbicarbonate solution yielded an ethereal solution of phenyl1-(4-bromophenyl)-1-phenyl-2-propyny1 carbonate. This solution was addedrapidly with stirring to 400 ml. of anhydrous liquid ammonia. The liquidammonia was allowed to evaporate over a 4-hour period and was replacedwith an equal volume of ether. The ethereal residue was washed withcold, dilute (5 N) sodium hydroxide, dried, and the solvents removed invacuo. The residual l-(4-bromophenyl)-1-phenyl-2-propynyl carbamate wasrecrystallized from benzene and melted at about 137139 C.

The following compounds, which can be prepared by this procedure, wereused in the hereinafter described examples:

1,1-diphenyl-2-propynyl N,N-dimethylcarbamate; melting point: 100-102 C.

l- (4-fiuor0phenyl) -1-phenyl-2-propynyl N-cyclohexyl-carbamate; meltingpoint: 167169 C.

1-(4-chlorophenyl) -1-phenyl-2-propynyl carbamate; melting point:169-171 C.

1,1-diphenyl-2-propynyl N-cyclohexylcarbamate; melting point: 155157 C.

The following examples illustrate the procedures available for thepreparation of the compounds of this invention.

EXAMPLE I 1,1-diphenylallyl N,N-dimethylcarbamate1,1-dipheny1-2-propynyl N,N-dirnethylcarbamate (27.9 g.) washydrogenated in a 4:1 mixture of benzene-petroleum ether (boiling point86-100 C.) using 0.5 g. palladium on barium sulfate and 0.5 g. powderedpotassium hydroxide as a catalyst. A hydrogen pressure of 40 p.s.i.g.was applied to the solution in an autoclave for 45 minutes. After theuptake of one-tenth mole of hydrogen, the solution was removed from theautoclave, filtered, the solvent removed in vacuo, and the residuerecrystallized from petroleum ether (boiling point 30-60 C.) Theresulting 1,1-diphenylallyl N,N-dimethylcarbamate (7.5 g.) melted atabout 102104 C.

The following compounds were prepared by the method of Example I usingthe appropriately substituted propargyl carbamate.

1- (4-fluoropheny1) -1-phenylallyl N-cyclohexylcarbamate;

melting point: 165-167 C.

1 (4 chlorophenyl)-l-phenylallyl carbamate; melting point: 111-113 C.

4 EXAMPLE II 1,1-diphenylallyl N-cyclohexylcarbamate1,1-diphenyl-2-propynyl N-cyclohexylcarbamate was reduced by the methodof Example I except that a mixture of methanolic ethyl acetatecontaining 1.0 g. quinoline was used as solvent. The product obtainedafter recrystallization, 1,1 diphenylallyl N-cyclohexylcarbamate, meltedat 152154 C.

1 (4 fluorophenyl) 1 phenylallyl N-cyclohexylcarbamate was also preparedby the method of Example II. Melting point 167 C.

EXAMPLE III 1- (4-fluorophenyl) -1-phenylallyl N-cyclohexylcarbamateFollowing the method of Example II, 1-phenyl-1-(4-fiuorophenyl)-2-propyn-1-ol was converted to l-phenyl-l-(4-fluorophenyl)-2-pr0pen-1-ol. Boiling point 1121l5 C./0.1 mm. Hg.

A solution of 22.8 g. of the abovemamed allyl alcohol in 50 ml. ofacetonitrile was treated with 16.5 ml. of cyclohexyl isocyanate and then2.8 g. of potassium carbonate. The resulting mixture was refluxed withstirring for one hour and allowed to cool to room temperature. Methylenechloride and water were added, the layers were separated, and theorganic layer was washed with water, dried, and the solvents removed invacuo. The resulting solid, 1-(4-fluorophenyl)-1-phenylallylN-cyclohexylcarbamate, was recrystallized from a mixture of benzene andpetroleum ether (boiling point 3@60 C.) Melting point 165167 C.

1,1-bis(4-fluoropheny1)allyl N-cyclohexylcarbamate was also prepared bythe method of Example III. Melting point 164-166 C.

The compounds of this invention have several pharmacological andbiological properties in common. One of these beneficial properties isthe ability to prevent the growth of certain bacteria and fungi invitro. Several examples of organisms so inhibited include Staphylococcusaureus, Bacillus subtilis, Mycobacterium avium, Vibrio metschnikovii,Trz'chophyton mentagrophytes, Scleroinia fructicola, and certain algae,as for example, T etrahymena pyriformis and Ochromonas malhamensis. Thisactivity can be obtained by contacting the growing bacteria with anaqueous suspension or solution of the compound at a concentration of10100 ug/ml. A second beneficial property of the compounds of thisinvention is their antiviral activity. The activity manifests itselfespecially against influenza virus in infected live mice.

We claim:

1. A compound represented by the following formula:

wherein R R and R are hydrogen, C -C alkyl, C -C hydroxyalkyl,di-lower-alkylamino-lower alkyl, C -C alkenyl, C C alkynyl, C Ccycloalkyl, or

C -C bicycloalkyl.

2. A compound as in claim 1, said compound being1-(4-chlorophenyl)-1-phenylallyl carbamate.

3. A compound as in claim 1, said compound being 1,1-diphenyla1lylN,N-dimethylcarbamate.

4. A compound as in claim 1, said compound being 1',1-diphenylallylN-cyclohexylcarbamate.

5. A compound as in claim 1, said compound being1-(4-fiuorophenyl)-1-phenylallyl N-cyclohexylcarbamate.

6. A compound as in claim 1, said compound being 1,1-bis(fiuorophenyl)allyl N-cyclohexylcarbamate.

6 References Cited UNITED STATES PATENTS 3,340,294 9/1967 Richter et a1260482 3,133,902 5/1964 Denchfield et a1 260-775 LORRAINE A. WEINBERGER,Primary Examiner R. GERSTL, Assistant Examiner US. Cl. X.R.

